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Nat Med. 2015 Jun;21(6):619-27. doi: 10.1038/nm.3862. Epub 2015 May 18.

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes.

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1] Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland. [2] Competence Center for Systems Physiology and Metabolic Disease, Swiss Federal Institute of Technology, Zurich, Switzerland.
Cell Isolation and Transplantation Center, Department of Surgery, University Hospitals and University of Geneva, Geneva, Switzerland.
Université de Lille 2, INSERM, European Genomic Institute for Diabetes, Lille Cedex, France.
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.


Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.

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